Design, synthesis and biological evaluation of 3,4-diaryl-1,2,5-oxadiazole-2/5-oxides as highly potent inhibitors of tubulin polymerization.

Abstract:

:Structure-activity relationships for rigid analogues of combretastatin A-4 (CA-4) were investigated, leading to the discovery of a series of 3,4-diaryl-1,2,5-oxadiazole-N-oxides. Among them, 7n' and 7n'' showed remarkable antiproliferative activities against three cancer cell lines in nanomolar concentrations. Interestingly, 7n' inhibited tubulin polymerization much more efficiently than CA-4. Cellular mechanism investigation elucidated 7n' disrupted the cellular microtubule structure, arrested cell cycle at G2/M phase and induces apoptosis. Molecular modeling study revealed 1,2,5-oxadiazole-N-oxide ring could increase a hydrogen bond interaction with the binding site. These results provide impetus and further guidance for the development of new CA-4 analogues.

journal_name

Eur J Med Chem

authors

Hong Y,Zhao Y,Yang L,Gao M,Li L,Man S,Wang Z,Guan Q,Bao K,Zuo D,Wu Y,Zhang W

doi

10.1016/j.ejmech.2019.05.036

subject

Has Abstract

pub_date

2019-09-15 00:00:00

pages

287-296

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(19)30446-5

journal_volume

178

pub_type

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